Dou Liu, Gavins Francesca K H, Mai Yang, Madla Christine M, Taherali Farhan, Orlu Mine, Murdan Sudaxshina, Basit Abdul W
UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK.
School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou 510275, China.
Pharmaceutics. 2020 Mar 25;12(4):296. doi: 10.3390/pharmaceutics12040296.
The rat is one of the most commonly used animal models in pre-clinical studies. Limited information between the sexes and the effect of food consumption on the gastrointestinal (GI) physiology, however, is acknowledged or understood. This study aimed to investigate the potential sex differences and effect of food intake on the intestinal luminal fluid and the efflux membrane transporter P-glycoprotein (P-gp) along the intestinal tract of male and female Wistar rats. To characterise the intestinal luminal fluids, pH, surface tension, buffer capacity and osmolality were measured. Absolute P-gp expression along the intestinal tract was quantified via liquid chromatography-tandem mass spectrometry (LC-MS/MS). In general, the characteristics of the luminal fluids were similar in male and female rats along the GI tract. In fasted male rats, the absolute P-gp expression gradually increased from the duodenum to ileum but decreased in the colon. A significant sex difference ( < 0.05) was identified in the jejunum where P-gp expression in males was 83% higher than in females. Similarly, ileal P-gp expression in male rats was approximately 58% higher than that of their female counterparts. Conversely, following food intake, a significant sex difference (p < 0.05) in P-gp expression was found but in a contrasting trend. Fed female rats expressed much higher P-gp levels than male rats with an increase of 77% and 34% in the jejunum and ileum, respectively. A deeper understanding of the effects of sex and food intake on the absorption of P-gp substrates can lead to an improved translation from pre-clinical animal studies into human pharmacokinetic studies.
大鼠是临床前研究中最常用的动物模型之一。然而，关于性别之间以及食物摄入对胃肠道（GI）生理学影响的信息却鲜为人知或未得到充分理解。本研究旨在调查雄性和雌性Wistar大鼠肠道中肠腔液以及外排膜转运蛋白P-糖蛋白（P-gp）的潜在性别差异和食物摄入的影响。为了表征肠腔液，测量了pH值、表面张力、缓冲能力和渗透压。通过液相色谱-串联质谱法（LC-MS/MS）对肠道中P-gp的绝对表达进行定量。总体而言，雄性和雌性大鼠沿胃肠道的肠腔液特征相似。在禁食的雄性大鼠中，P-gp的绝对表达从十二指肠到回肠逐渐增加，但在结肠中降低。在空肠中发现了显著的性别差异（<0.05），雄性大鼠的P-gp表达比雌性高83%。同样，雄性大鼠回肠中的P-gp表达比雌性大鼠高约58%。相反，进食后，P-gp表达存在显著的性别差异（p<0.05），但趋势相反。喂食的雌性大鼠表达的P-gp水平比雄性大鼠高得多，空肠和回肠中的表达分别增加了77%和34%。对性别和食物摄入对P-gp底物吸收影响的更深入理解可以改善从临床前动物研究到人体药代动力学研究的转化。
